Epigenetic mechanisms underlying stress‐induced visceral pain: Resilience versus vulnerability in a two‐hit model of early life stress and chronic adult stress

Abstract

Background Women with a history of early life stress (ELS) have a higher risk of developing irritable bowel syndrome (IBS). In addition, chronic stress in adulthood can exacerbate IBS symptoms such as abdominal pain due to visceral hypersensitivity. We previously showed that sex and the predictability of ELS determine whether rats develop visceral hypersensitivity in adulthood. In female rats, unpredictable ELS confers vulnerability and results in visceral hypersensitivity, whereas predictable ELS induces resilience and does not induce visceral hypersensitivity in adulthood. However, this resilience is lost after exposure to chronic stress in adulthood leading to an exacerbation of visceral hypersensitivity. Evidence suggests that changes in histone acetylation at the promoter regions of glucocorticoid receptor (GR) and corticotrophin‐releasing factor (CRF) in the central nucleus of the amygdala (CeA) underlie stress‐induced visceral hypersensitivity. Here, we aimed to investigate the role of histone acetylation in the CeA on visceral hypersensitivity in a two‐hit model of ELS followed by chronic stress in adulthood. Methods Male and female neonatal rats were exposed to unpredictable, predictable ELS, or odor only (no stress control) from postnatal days 8 to 12. In adulthood, rats underwent stereotaxic implantation of indwelling cannulas. Rats were exposed to chronic water avoidance stress (WAS, 1 h/day for 7 days) or SHAM stress and received infusions of vehicle, the histone deacetylase inhibitor trichostatin A (TSA) or the histone acetyltransferase inhibitor garcinol (GAR) after each WAS session. 24 h after the final infusion, visceral sensitivity was assessed and the CeA was removed for molecular experiments. Results In the two‐hit model (ELS + WAS), female rats previously exposed to predictable ELS, showed a significant reduction in histone 3 lysine 9 (H3K9) acetylation at the GR promoter and a significant increase in H3K9 acetylation at the CRF promoter. These epigenetic changes were associated with changes in GR and CRF mRNA expression in the CeA and an exacerbation of stress‐induced visceral hypersensitivity in female animals. TSA infusions in the CeA attenuated the exacerbated stress‐induced visceral hypersensitivity, whereas GAR infusions only partially ameliorated ELS+WAS induced visceral hypersensitivity. Conclusion The two‐hit model of ELS followed by WAS in adulthood revealed that epigenetic dysregulation occurs after exposure to stress in two important periods of life and contributes to the development of visceral hypersensitivity. These aberrant underlying epigenetic changes may explain the exacerbation of stress‐induced abdominal pain in IBS patients.

Stress-Induced Changes in the Endogenous Opioid System Cause Dysfunction of Pain and Emotion Regulation

“…Burke et al, claimed that 24-h mother-infant separation on postnatal day 9 exacerbated neuropathic pain in female mice during maturation [54]. ELS is known to exacerbate not only neuropathic pain but also fibromyalgia [55] and abdominal pain, which are associated with irritable bowel syndrome (IBS) [56,57]. However, there are few reports on the involvement of the altered function of opioid receptors and changes in their receptor expression in the mechanism for ELS-induced fibromyalgia and IBS-induced abdominal pain.…”

“…Women with a history of ELS have a higher risk of developing irritable bowel syndrome [56,57] Clinical Cross-sectional analysis of the 2016-2017 National Survey of Children's Health…”